QOL Assessment in Rheumatoid Arthritis 839 etes with the natural IL-I ligand for eriod of months but since binding sites.it does not itself induce signal trans. duction after binding.s51 Anakinra is indicated for fits.with the reduction in signs and symptoms and slowing preliminary evidence suggesting the clinical bene. the progression of structural damage in adults with fits of such re-treatment in some patients.0 Ritux imab is indicated for use in exate in adult pati erately to review anak a on severely active RA who ed to one agents squate cluded was a t effects of rituximab plus methotrexate comp re Health Profile as well as changes in productivi- with placebo plus methotrexate in a randomized ty. 51 This review reported that,among the studies clinical trial.HR-QOL outcomes included the HAQ that incorporated the HAQ as an outcome,use of DI,the SF-36 and the Functional Assessment of F).m -Fatigue Scale (FACIT proven lated HR-QOl After weeks o rapy ce These reported clinic ant improv AO-D than those obtained with placebo.The study that change in the placebo g In addition.patients in incorporated the Nottingham Health Profile as an p rep oved sc res on the outcome showed that the improvements in the pain. SF-36 and sig ificant reduction in fatigue as mea energy.physical mobility and emotional reactions sured by FACIT-F.with a mean change from base subs ales obtained at 24 weeks of treatment with line that exceeded the MCID.Patients in the placebo antly greater than with place group had only slight improvements in fatigue and re lated ments SE36 statis cally nong patie 5.5 Rituximab 5.6 Abatacept Despite der strated improvements in clinical Abatacept,another biological DMARD with a L in patients treated with anti many pa are ory no trea ae no t uncom or that b h othe definition of failur to he safe ell t ed and able it has been reported that 25-30%of patients fail to a significant dose-den ndent reduction in disease respond to these agents.o activity in patients with RA.Abatacept is indicat. Rituximab is a genetically engineered,chimeric ed for reducing signs and symptoms of RA.inducing (murine/human)monoclonal antibody with a target major clinical response,inhibiting the progression f structu al damage and improving physical fu s.It is directed inst the CD20 anti rately to severely active R gen fo on the su a sing acept may anti-TNFo denlet lation n a phase mib clinical trial evaluating the efficacy dependent cell-mediated cvtotoxicity and con of abatacept 2 mg/kg and abatacept 10 mg/kg in ment-dependent cytotoxicity.B-cell depletion is combination with methotrexate compared with e 2008 Ads Data loform ation BV.All rights reserved conomics 2008:26 (10)
QOL Assessment in Rheumatoid Arthritis 839 competes with the natural IL-1 ligand for receptor sustained over a period of months, but since repopubinding sites, it does not itself induce signal trans- lation occurs,[69] multiple courses of therapy may be duction after binding.[55] Anakinra is indicated for required for maintenance of long-term benefits, with the reduction in signs and symptoms and slowing preliminary evidence suggesting the clinical benethe progression of structural damage in adults with fits of such re-treatment in some patients.[70] Rituxmoderately to severely active RA for whom therapy imab is indicated for use in combination with with one or more DMARDs has failed.[55] methotrexate in adult patients with moderately to The effects of anakinra on HR-QOL were recent- severely active RA who have had an inadequate response to one or more anti-TNFα agents.[54] ly reviewed,[64] primarily based on functional outcomes assessed using the HAQ, although also in- To investigate HR-QOL in patients refractory to cluded was a placebo controlled monotherapy study anti-TNFα therapy, Cohen et al.[71] evaluated the which evaluated HR-QOL using the Nottingham effects of rituximab plus methotrexate compared Health Profile as well as changes in productivi- with placebo plus methotrexate in a randomized ty.[64,65] This review reported that, among the studies clinical trial. HR-QOL outcomes included the HAQthat incorporated the HAQ as an outcome, use of DI, the SF-36 and the Functional Assessment of anakinra (compared with placebo) resulted in im- Chronic Illness Therapy-Fatigue Scale (FACITprovements in functionally related HR-QOL, as sug- F).[71] After 24 weeks of therapy, patients who regested by both the total HAQ score and individual ceived rituximab reported clinically meaningful and components. These improvements were clinically statistically significant improvements in HAQ-DI relevant and, in general, were significantly greater scores from baseline compared with little or no than those obtained with placebo. The study that change in the placebo group. In addition, patients in incorporated the Nottingham Health Profile as an the rituximab group reported improved scores on the outcome showed that the improvements in the pain, SF-36 and significant reduction in fatigue as meaenergy, physical mobility and emotional reactions sured by FACIT-F, with a mean change from basesubscales obtained at 24 weeks of treatment with line that exceeded the MCID. Patients in the placebo anakinra were significantly greater than with place- group had only slight improvements in fatigue and bo.[64,65] A dose-related increase in productivity was lesser, but still statistically significant, improvealso observed among patients receiving anakinra. ments in SF-36 scores from baseline.[71] 5.5 Rituximab 5.6 Abatacept Despite demonstrated improvements in clinical Abatacept, another biological DMARD with a efficacy and HR-QOL in patients treated with anti- mechanism of action different from the anti-TNFα TNFα therapies, many patients are refractory to agents, is a novel selective T-cell co-stimulation these agents, and treatment failures are not uncom- modulator that blocks the co-stimulatory signal remon. Although the proportion of patients for whom quired for activation of T cells. Abatacept has been therapy fails may depend on the definition of failure, shown to be safe, well tolerated and able to produce it has been reported that 25–30% of patients fail to a significant dose-dependent reduction in disease respond to these agents.[66,67] activity in patients with RA.[72] Abatacept is indicatRituximab is a genetically engineered, chimeric ed for reducing signs and symptoms of RA, inducing (murine/human) monoclonal antibody with a target major clinical response, inhibiting the progression and mechanism of action different from the anti- of structural damage and improving physical funcTNFα agents. It is directed against the CD20 anti- tion in adults with moderately to severely active RA. gen found on the surface of B cells, and a single Abatacept may be used as monotherapy or concomicourse of treatment with rituximab results in a rapid, tantly with DMARDs other than anti-TNFα agents.[53] selective and transient depletion of the B-cell population via several mechanisms, including antigen- In a phase IIb clinical trial evaluating the efficacy dependent cell-mediated cytotoxicity and comple- of abatacept 2 mg/kg and abatacept 10 mg/kg in ment-dependent cytotoxicity.[68] B-cell depletion is combination with methotrexate compared with © 2008 Adis Data Information BV. All rights reserved. Pharmacoeconomics 2008; 26 (10)
840 Russell Table ll.Dat double-blind clini o plus met ered for upt of pts) 12m0 PE Any limitations in walking ooe block RP amount of 66 46 74 45 70 32 BP Pain in fered with work quite a bit or 56 21 21 51 Fair or poor rating of health in general 33 63 39 64 Felt tired all or most of the tim 40 20 ctivities quite a 35 39 RE 57 36 51 32 42 23 MH Fe downhearted and blue all or most of the10 7 22 11 18 4 than 6 of the 01 culty a limit (729 7sF-36 e at red with 42%at 12 months)versus no reduction domains were observed to be 1.5-2.0 standard devi- (61%at baseline vs 62%at 12 months)for placebo ations below general population norms and below (table ID.Similarly,nearly all individual items the average scores of people aged 285 years.The from other domains also showed greater reductions emotional burden of RA was also suggested by the with abatacept than with placebo (table ID).73 The Dercentage of patients who cut down the amount o and mental summary m sure,which were at t 12 months was 5 cut-p for s epres no SE-6D was which demon and placeb In this study.improvement in HR-QOL was mately n-half between 0.55 and 0.57 among the response After 12 months of treatment,statistically signif S wel health and role acep correlated to ACR improvement than were those measuring mental health status.731 nts in HR-OOLi ments in HR-QOL with abatacep pt in a treatment g up.In addition.abatac 10m ents whose ra was refrac plus methotrexate also resulted in significantly tory to methotrexate therany have been reported in a better HR-QOL outcomes than the lower dose.Con- phase III trial.This trial,a randomized,double-blind tent-based interpret on of specific individual items clinical study in 652 patients with RA,evaluated from the different SF-36 dom uns was used to c actenze up to I year ences. tha rlying these differ among patients HAQ-DI analogue scale for fatigue -ho
840 Russell Table II. Data from a randomized, double-blind clinical study in 652 patients (pts) given either abatacept 10 mg/kg or 2 mg/kg plus methotrexate or placebo plus methotrexate, administered for up to 1 year; percentage of pt with rheumatoid arthritis reporting limitations in functional status and well-being (content-based interpretations of changes in SF-36 scale scores)[73] SF-36 Selected item content as dichotomized Placebo Abatacept 2 mg/kg + Abatacept 10 mg/kg + scale (% of pts) methotrexate (% of pts) methotrexate (% of pts) BL 12 mo BL 12 mo BL 12 mo PF Any limitations in walking one block 61 62 69 49 72 42 RP Cut down amount of time spent on work/ 66 46 74 45 70 32 activities BP Pain interfered with work quite a bit or 56 21 61 21 51 11 extremely GH Fair or poor rating of health in general 64 33 62 39 64 26 VT Felt tired all or most of the time 39 31 40 20 38 14 SF Health interferes with social activities quite a 35 16 39 14 32 9 lot or extremely RE Did not do work/activities as carefully as 57 36 51 32 42 23 usual MH Felt downhearted and blue all or most of the 10 7 22 11 18 4 time BL = baseline; BP = bodily pain; GH = general health; MH = mental health; PF = physical function; RE = role-emotional; RP = role-physical; SF = social functioning; VT = vitality. methotrexate alone,[72] Emery et al.[73] found that who received abatacept 10 mg/kg plus methotrexate, more than 60% of the patients reported functional there was an approximately 40% relative reduction limitations at baseline, including difficulty walking in the proportion of patients who reported a limitaone block or decreased time at work due to physical tion in walking one block (72% at baseline comhealth problems. pared with 42% at 12 months) versus no reduction [73] SF-36 scores for physical health domains were observed to be 1.5–2.0 standard devi- (61% at baseline vs 62% at 12 months) for placebo (table II).[73] ations below general population norms and below Similarly, nearly all individual items the average scores of people aged ≥85 years. The from other domains also showed greater reductions with abatacept than with placebo (table II).[73] emotional burden of RA was also suggested by the The average baseline scores on the SF-36 mental health percentage of patients who cut down the amount of scale and mental summary measure, which were at time spent at work/activities at 12 months was 32% the cut-point score for stage 1 depression. Addition- and 46% in the abatacept 10 mg/kg and placebo groups, respectively.[73] ally, a substantial overall burden was also demonstrated by the baseline SF-6D score, which ranged In this study, improvement in HR-QOL was between 0.55 and 0.57 among the groups; approxi- closely related to clinical response to abatacept. mately one-half of optimal health.[73] However, improvements from baseline on SF-36 After 12 months of treatment, statistically signif- scales measuring physical health status (physical summary, bodily pain, physical functioning, general icant differences were observed in the eight domains health and role physical scales) were more closely and two summary measures of the SF-36, as well as correlated to ACR improvement than were those the SF-6D score, for the group receiving abatacept measuring mental health status.[73] 10 mg/kg plus methotrexate compared with placebo, suggesting greater improvements in HR-QOL in this Improvements in HR-QOL with abatacept in a treatment group.[73] In addition, abatacept 10 mg/kg similar population of patients whose RA was refracplus methotrexate also resulted in significantly tory to methotrexate therapy have been reported in a better HR-QOL outcomes than the lower dose. Con- phase III trial. This trial, a randomized, double-blind tent-based interpretation of specific individual items clinical study in 652 patients with RA, evaluated from the different SF-36 domains was used to char- abatacept 10 mg/kg plus methotrexate or placebo acterize the improvements underlying these differ- plus methotrexate for up to 1 year.[74] The SF-36, ences. This analysis showed that, among patients HAQ-DI and a visual analogue scale for fatigue © 2008 Adis Data Information BV. All rights reserved. Pharmacoeconomics 2008; 26 (10)
QOL Assessment in Rheumatoid Arthritis 841 were used to assess HR-QOL.74 At baseline.SF-36 te or scores showed that these patients had a high disease burden in both physical and mental health domains compared with the general population.74 DMARD (an oral DMARD or anakinra;n=258)or Treatment with abatacep plus methotrexate for placebo plus DMARD (n=133)for 6 months.!751 In 12 months resulted in significantly greater improve- S6Roo were s da 29a d the SF nent in physical function. reflected by a cha from baseline in the HAQ-DI meeting or exceeding greater proportion of patients in the abatacept plus the MCID of 0.3,was evident in a significantly methotrexate group achieved or approached popula- greater proportion of patients in the abatacept group tion norms of HR-QOL than patients who received than group (47.3% 23.3% methotrexate alone." As p<0.0i patients in the nents From ore clinic a i油 in A SF-36 as well as on the physical and mental c HAO-DL and the nd mponent sum Westh HR-OOL out se et al isl evaluated the clinical efficad and safety of abatacept as well as its effect on HR- ers)trials in greater detail.After 6 months of QOL in patients with severe RA who had an inade- treatment,significantly greater improvements in all 10 ublb Pain ent compone 0.001 vs placebo 2008 Adis Data Information BV.All rights resorved Phamocooconomics 2008:26 (10)
QOL Assessment in Rheumatoid Arthritis 841 were used to assess HR-QOL.[74] At baseline, SF-36 quate or unsustained response to at least 3 months’ scores showed that these patients had a high disease therapy with anti-TNFα therapy.[75] Patients were burden in both physical and mental health domains randomized in a 2 : 1 ratio to abatacept plus another compared with the general population.[74] DMARD (an oral DMARD or anakinra; n = 258) or placebo plus DMARD (n = 133) for 6 months.[75] Treatment with abatacept plus methotrexate for In 12 months resulted in significantly greater improve- addition to ACR clinical response criteria, HAQ-DI and SF-36 were also assessed.[75] ment in all HR-QOL outcome measures including After 6 months, SF-36 domains, patient function (HAQ-DI) and fa- the proportion of patients who achieved each level tigue, than with methotrexate monotherapy. Signif- of ACR response (20%, 50% and 70%) was signifiicant differences between the two groups were ob- cantly greater in the abatacept group than in the placebo group.[75] served as early as day 29 for fatigue and the SF-36 A clinically meaningful improvedomains of bodily pain, role physical, general ment in physical function, reflected by a change health, vitality and social role.[74] A significantly from baseline in the HAQ-DI meeting or exceeding greater proportion of patients in the abatacept plus the MCID of 0.3, was evident in a significantly methotrexate group achieved or approached popula- greater proportion of patients in the abatacept group tion norms of HR-QOL than patients who received than in the placebo group (47.3% vs 23.3%; p < 0.01).[75] methotrexate alone. Additionally, patients in the abatacept [74] As in the phase IIb study reported by Emery et al.,[73] improvements from group had significantly higher and more clinically baseline in HR-QOL outcomes appeared to correlate meaningful changes in all eight domains of the with improvement in ACR clinical criteria, with SF-36 as well as on the physical and mental component summary scores, as shown in figure 2.[75] particularly strong correlations demonstrated for the HAQ-DI and the pain and physical component sum- Westhovens et al.[76] examined HR-QOL outmary scores on the SF-36.[74] comes of patients from the ATTAIN (Abatacept Genovese et al.,[75] evaluated the clinical efficacy Trial in treatment of Anti-TNF Inadequate Respondand safety of abatacept as well as its effect on HR- ers) trial[75] in greater detail. After 6 months of QOL in patients with severe RA who had an inade- treatment, significantly greater improvements in all 0 1 2 3 4 5 6 7 8 9 10 Physical function Mean change in SF-36 score from baseline Physical role Pain General health Vitality Social function Emotional role Mental health Physical component summary Mental component summary Abatacept (n = 246) Placebo (n = 133) ** *** * *** *** *** *** *** *** * Fig. 2. Effect of abatacept compared with placebo on health-related quality of life at 6 months evaluated using the SF-36. Reproduced from Genovese et al.,[75] with permission. Copyright © [2005] Massachusetts Medical Society. All rights reserved. * p <0.05, ** p < 0.01, *** p < 0.001 vs placebo. © 2008 Adis Data Information BV. All rights reserved. Pharmacoeconomics 2008; 26 (10)